2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9h-pyrido (3,4-b) indole-3-carboxylic acid esters/amides useful as antithrombotic agents

ABSTRACT

The present invention relates to antithrombotic compounds 2-alkyl aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid esters/amides, pharmaceutically acceptable salts and compositions thereof to be used in the treatment of intravascular thrombosis such as myocardial ischemia and stroke. The compound has the following general structure  
                 
 
wherein R represents methyl ester or amide and R 1  represents alkyl, aryl and heteroaryl moiety.

FIELD OF THE INVENTION

The present invention relates to antithrombotic compounds 2-alkyl arylsulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acidesters/amides, pharmaceutically acceptable salts and compositionsthereof useful in treatment of intravascular thrombosis such asmyocardial ischemia and stroke. The compound has the following generalstructure

wherein R represents methyl ester or amide and R₁ represents alkyl, aryland heteroaryl moiety. The present invention particularly relates tonovel compounds 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid esters/amides, which are potentantithrombotic agents and can be useful in treatment of intravascularthrombosis, such as myocardial ischemia and stroke. The presentinvention also relates to processes for preparing the said novelcompounds. More particularly the present invention relates to2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)indole-3-carboxylic acid esters/amides, processes for preparing the saidcompounds and to their use in medicine.

BACKGROUND OF THE INVENTION AND PRIOR ART

Cardiovascular diseases associated with intravascular thrombosis are themost common cause of death in both developed and developing countries.Arterial and venous thromboses are the principal causes for theevolution of myocardial infarction, thromboembolic stroke and deep veinthrombosis. Approximately three million individuals die each year in theUnited States only from venous (deep vein thrombosis and pulmonaryembolism) or arterial thrombosis (acute myocardial infarction andunstable angina).

Initiation of thrombosis is a complex process. The final event i.e. thethrombus formation, however, is primarily due to the activation ofplatelets and coagulation cascade. Clinical and experimental studiesindicate that abnormalities in the normal blood flow, activation ofplatelets, coagulation cascade or fibrinolysis contribute to thepathogenesis of intravascular thrombosis/thromboembolism. Though thetreatment strategy for thrombosis has improved with newer diagnostic andsurgical tools but effective antithrombotic therapy with minimal sideeffects still poses a challenge to scientists around the globe.

Antithrombotic agents have been researched and developed for use intreating cardiovascular and other diseases. Presently establishedantithrombotic agents include heparin, coumarin, and aspirin. There are,however, limitations with these agents. For example, both heparin¹ andcoumarin² have a highly-variable dose-related response, and theiranticoagulant effects must be closely monitored to avoid a risk ofserious bleeding. The erratic anticoagulant response of heparin islikely due to its propensity to bind non-specifically to plasmaproteins. Aspirin has a limited efficacy and at high doses presents arisk of gastrointestinal bleeding.

Tissue plasminogen activators^(3,4), platelet GPIIb/IIIa antagonists⁵,ADP receptor antagonists⁶, are also being currently used to treatthrombosis, however, these drugs have some inherent problems andlimitations. Therefore, new search is taken up to develop nextgeneration anti-thrombotic agents such as direct thrombin inhibitors⁷,tissue factor pathway inhibitors⁸, Factor Xa inhibitors⁹, collagenantagonists¹⁰ and gene therapy. The search of a potent orally active andspecific anti-thrombotic agent with minimal danger of bleeding orunrelated side effects is thus an area of interest. Moreover, the highcost of anticoagulant and antithrombotic therapy necessitates the searchfor efficacious new chemical entities.

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OBJECTS OF THE INVENTION

The main object of the invention is to provide novel molecules2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)indole-3-carboxylic acid esters/amides that exhibit better therapeuticefficacy to treat intravascular thrombosis, myocardial ischemia andstroke over the existing antithrombotic agents.

It is another object of the invention to provide novel 2-alkyl/arylsulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylicacid esters/amides exhibiting activity against intravascular thrombosisfor which there is/are no/few agent/agents available till date.

It is another object of the invention to provide 2-alkyl/arylsulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylicacid esters/amides as therapeutic agents for diseases arising out ofalterations/impairment in intravascular thrombosis leading to myocardialischemia and stroke.

It is another object of the invention to provide a process for preparingnovel 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b)indole-3-carboxylic acid esters/amides.

It is another object of the invention to provide a pharmaceuticalcomposition comprising 2-alkyl/aryl sulphonyl-1, 2, 3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters/amidesand pharmaceutically acceptable additive(s) and a process for preparingsuch composition.

It is another object of the invention to provide for the use ofcompounds of the present invention in the treatment or prevention ofprimary arterial thrombotic complications of atherosclerosis such asthrombotic stroke, peripheral vascular disease, and myocardialinfarction without thrombolysis.

It is another object of the invention to provide for the use ofcompounds of the invention for the treatment or prevention of arterialthrombotic complications due to interventions in atherosclerotic diseasesuch as angioplasty, endarterectomy, stent placement, coronary and othervascular graft surgery.

It is another object of the invention to provide for the use of thecompounds of the invention for the treatment or prevention of thromboticcomplications of surgical or mechanical damage such as tissue salvagefollowing surgical or accidental trauma, reconstructive surgeryincluding skin flaps, and “reductive” surgery such as breast reduction.

It is another object of the invention to provide for the use ofcompounds of the present invention for the prevention ofmechanically-induced platelet activation in vivo such as cardiopulmonarybypass (prevention of microthromboembolism), prevention ofmechanically-induced platelet activation in vitro such as the use of thecompounds in the preservation of blood products, e.g. plateletconcentrates, prevention of shunt occlusion such as renal dialysis andplasmapheresis, thrombosis secondary to vascular damage/inflammationsuch as vasculitis, arteritis, glomerulonephritis and organ graftrejection.

It is another object of the invention to provide for the use ofcompounds of the present invention for the indicating with a diffusethrombotic/platelet consumption component such as disseminatedintravascular coagulation, thrombotic thrombocytopenic purpura,hemolytic uremic syndrome, heparin-induced thrombocytopenia andpre-eclampsia/eclampsia.

It is another object of the invention to provide for the use ofcompounds of the present invention for the treatment or prevention ofvenous thrombosis such as deep vein thrombosis, veno-occlusive disease,hematological conditions such as thrombocythemia and polycythemia, andmigraine.

It is another object of the invention to provide for the use ofcompounds of the present invention in treatment of unstable angina,coronary angioplasty and myocardial infarction.

It is another object of the invention to provide for the use ofcompounds of the present invention for adjunctive therapy in theprevention of coronary arterial thrombosis during the management ofunstable angina, coronary angioplasty and acute myocardial infarction,i.e. perithrombolysis.

It is another object of the invention to provide for a method oftreating mammals to alleviate the pathological effects ofatherosclerosis and arteriosclerosis, acute MI, chronic stable angina,unstable angina, transient ischemic attacks and strokes, peripheralvascular disease, arterial thrombosis, preeclampsia, embolism,restenosis or abrupt closure following angioplasty, carotidendarterectomy, and anastomosis of vascular grafts.

It is another object of the invention to provide for the use ofcompounds of the present invention in vitro to inhibit the aggregationof platelets in blood and blood products, e.g. for storage, or for exvivo manipulations such as in diagnostic or research use.

It is another object of the invention to provide for the use ofcompounds of the present invention for the to inhibit plateletaggregation and clot formation in a mammal, especially a human, whichcomprises the internal administration.

It is another object of the invention to provide for the use ofcompounds of the present invention for the treatment of chronic or acutestates of hyperaggregability, such as disseminated intravascularcoagulation (DIC), septicemia, surgical or infectious shock,post-operative and post-partum trauma, cardiopulmonary bypass surgery,incompatible blood transfusion, abruptio placenta, thromboticthrombocytopenic purpura (TTP), snake venom and immune diseases, whichare likely to be responsive to these compounds.

It is another object of the invention to provide for the use ofcompounds of the present invention in a method for inhibiting thereocclusion of an artery or vein following fibrinolytic therapy, whichcomprises internal administration of compound and a fibrinolytic agent.

It is another object of the invention to provide for the use ofcompounds of the present invention for extracorporeal circulation, whichis routinely used for cardiovascular surgery in order to oxygenateblood. Platelets adhere to surfaces of the extracorporeal circuit.

It is another object of the invention to provide for the use ofcompounds of the present invention for prevention of plateletthrombosis, thromboembolism and reocclusion during and afterthrombolytic therapy and prevention of platelet thrombosis,thromboembolism and reocclusion after angioplasty of coronary and otherarteries and after coronary artery bypass procedures.

To achieve the above and other objects the present invention providesnovel pharmacologically active compounds, specifically new 2-alkyl arylsulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acidesters/amides which are used as potential therapeutic agents forintravascular thrombosis, myocardial ischemia and stroke and otherdisorders as mentioned above.

SUMMARY OF THE INVENTION

Accordingly the present invention relates to 2-alkyl/arylsulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acidesters/amides having formula 1:

wherein R is selected from methyl ester and amide; and R₁ is selectedfrom the group consisting of alkyl, aryl, and heteroaryl moiety.

In one embodiment of the invention, the compound comprises at least oneof:

-   -   a. 2[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   b. 2[2,4,6, trimethyl benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   c. 2[2,nitrobenzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   d. 2[1-napthyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid ester    -   e. 2-4-metoxy benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3        ,4-b] indole-3-carboxylic acid ester    -   f. 2[8-quinoline sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic 0 acid ester    -   g. 2-[dansyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid ester    -   h. 2[2,4,6 tri isopropyl benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   i. 2[4-floro benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   j. 2[2-tri floro methyl benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   k. 2[methyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid ester    -   l. 2-[2-napthalene sulfonyl]-1, 2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   m. 2[benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid ester    -   n. 2[4-methyl benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester

In other embodiment the compound includes at least one of:

-   -   o. 2[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   p. 2[-4-methoxy benzene sulfonyl]-1,2,3 ,4,-tetra        hydro-9H-pyrido[3 ,4-b] indole-3-carboxylic acid amide    -   q. 2[-1-napthylsulfonyl]-1,2,3 ,4,-tetra hydro-9H-pyrido[3 ,4-b]        indole-3-carboxylic acid amide    -   r. 2[8-quinoline sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid amide    -   s. 2[-4-floro benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   t. 2[methane sulphonyl sulfonyl-1, 2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   u. 2[3-nitro benzene sulfonyl-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   v. 2[2,4,6 trimethyl benzene sulfonyl-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   w. 2-[2-napthalene sulfonyl]-1 ,2,3,4,-tetra hydro-9H-pyrido[3        ,4-b] indole-3-carboxylic acid amide

The present invention also provides a process for synthesis of2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b)indole-3-carboxylic acid esters/amides of formula 1:

wherein R is selected from methyl ester and amide; and R₁ is selectedfrom the group consisting of alkyl, aryl, and heteroaryl moiety, theprocess comprising condensing an alkyl or aryl sulphonyl chloridewherein aryl includes substituted phenyl substituted by group selectedfrom the group consisting of hydrogen, halogens, alkyl and alkoxy,substituted napthyl substituted by group selected from the groupconsisting of hydrogen and dimethyl amino; and heteroaryl like quinolinewith dimethyl-l, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)indole-3-carboxylate Formula 2 in the presence of a base and an organicsolvent at temperature ranging from 30° C. to 120° C. for 8 to 24 hoursto produce the corresponding 2-alkyl/aryl sulphonyl-1, 2, 3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters.

In another embodiment, the invention relates to a process for thesynthesis of the above compounds by condensing an alkyl or arylsulphonyl chloride where in aryl includes, substituted phenyl by groupslike hydrogens, halogens, alkyl, alkoxy etc., substituted napthyl byhydrogen, di methyl amino, and heteroaryl like quinoline with dl 1, 2,3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide formula 3 in thepresence of a base and an organic solvent at temperature ranging from30° C. to 120° C. for 8 to 24 hours to produce the corresponding2-alkyl/aryl sulphonyl-l, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)indole-3-carboxylic acid amides.

In another embodiment, the invention relates to a process for thesynthesis of the above compounds wherein 2-alkyl/aryl sulphonyl-1, 2, 3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters istreated with methanolic ammonia for 24 to 48 hours hrs to obtain thecorresponding 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid amides.

In another preferred embodiment, the synthesis of 2-alkyl/arylsulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylicacid esters/amide of formula 1 includes the presence of one of theorganic solvent selected from a group of acetone, DMF, THF, dioxane, abase including at least one of TEA, K₂CO₃, Na₂CO₃, pyridine and atemperature of about 30° C. to 120° C. for 8 to 24 hours.

In another embodiment, the molar ratios of the substituted sulphonylchloride to dl methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)indole-3-carboxylate/dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)indole-3-amide is about 1:2. In yet another preferred embodiment theorganic solvents include acetone, DMF, THF, dioxane and the organicsolvent is present about 0.8-2.2 ml per mmol.

In another embodiment, the molar ratio of the base to the dl methyl-I,2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate/dli 1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide is about 1:4.

The invention also relates to pharmaceutical compositions having thecompound of formula 1 described above in a mixture with apharmaceutically acceptable carrier. The invention further relates to aprocess for preparing the pharmaceutical composition by bringing thecompound into association with a pharmaceutically acceptable additive.

The invention also relates to method of treating various diseases withthe pharmaceutical compositions of the present invention. In oneembodiment, the method involves treating intravascular thrombosis inmammals by administering to a patient in need thereof a therapeuticallyeffective amount of the pharmaceutical composition. In one embodiment,the method involves treating myocardial ischemia in mammals, byadministering to a patient in need thereof a therapeutically effectiveamount of the pharmaceutical composition In one embodiment, the methodinvolves treating stroke in mammals, by administering to a patient inneed thereof a therapeutically effective amount of the pharmaceuticalcomposition.

In a preferred embodiment, the diseases treated are selected to beintravascular thrombosis, myocardial ischemia and stroke or acombination thereof. In another preferred embodiment the intravasculardiseases are selected to include as mentioned above. In anotherpreferred embodiment halogen of the compound is selected from the groupof chlorine, bromine fluorine and iodine, and mixtures thereof, thealkoxy is selected to be a C₁-C₁₀ oxy, the alkyl is selected to beC₁-C₁₀ alkyl, and the heteroaryl is selected to be a C₄-C₁₀ heteroaryl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the effect of compound (i) onhuman platelet aggregation.

DETAILED DESCRIPTION OF THE INVENTION

The compound of the present invention achieves the following objects:

-   -   i) providing novel molecules 2-alkyl/aryl sulphonyl-1, 2, 3,        4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid        esters/amides that may exhibit better therapeutic efficacy to        treat intravascular thrombosis, myocardial ischemia and stroke        over the existing antithrombotic agents.    -   ii) providing novel 2-alkyl/aryl sulphonyl-1, 2, 3,        4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid        esters/amides exhibiting activity against intravascular        thrombosis for which there is/are no/few agent/agents available        till date to the best of the applicants knowledge.    -   iii) providing 2-alkyl/aryl sulphonyl-1, 2, 3,        4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid        esters/amides as therapeutic agents for the diseases arising out        of alterations/impairment in intravascular thrombosis leading to        myocardial ischemia and stroke.    -   iv) providing processes for preparing novel 2-alkyl/aryl        sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)        indole-3-carboxylic acid esters/amides.    -   v) providing a pharmaceutical composition comprising        2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)        indole-3-carboxylic acid esters/amides. And pharmaceutically        acceptable additive (s) and a process for preparing such        composition.    -   vi) providing for use of the compounds in the treatment or        prevention of primary arterial thrombotic complications of        atherosclerosis such as thrombotic stroke, peripheral vascular        disease, and myocardial infarction without thrombolysis.    -   vii) providing for the use of the compounds of the invention for        the treatment or prevention of arterial thrombotic complications        due to interventions in atherosclerotic disease such as        angioplasty, endarterectomy, stent placement, coronary and other        vascular graft surgery.    -   viii) providing for the use of the compounds of the invention        for the treatment or prevention of thrombotic complications of        surgical or mechanical damage such as tissue salvage following        surgical or accidental trauma, reconstructive surgery including        skin flaps, and “reductive” surgery such as breast reduction.    -   ix) providing for the use of the compounds of the invention for        the prevention of mechanically-induced platelet activation in        vivo such as cardiopulmonary bypass (prevention of        microthromboembolism), prevention of mechanically-induced        platelet activation in vitro such as the use of the compounds in        the preservation of blood products, e.g. platelet concentrates,        prevention of shunt occlusion such as renal dialysis and        plasmapheresis, thrombosis secondary to vascular        damage/inflammation such as vasculitis, arteritis,        glomerulonephritis and organ graft rejection.    -   x) providing for the use of the compounds of the invention as        indicators with a diffuse thrombotic/platelet consumption        component such as disseminated intravascular coagulation,        thrombotic thrombocytopenic purpura, hemolytic uremic syndrome,        heparin-induced thrombocytopenia and pre-eclampsia/eclampsia.    -   xi) providing for the use of the compounds of the invention for        the treatment or prevention of venous thrombosis such as deep        vein thrombosis, veno-occlusive disease, hematological        conditions such as thrombocythemia and polycythemia, and        migraine.    -   xii) providing for the use of the compounds of the invention for        the treatment of unstable angina, coronary angioplasty and        myocardial infarction.    -   xiii) providing for the use of the compounds of the invention        for the adjunctive therapy in the prevention of coronary        arterial thrombosis during the management of unstable angina,        coronary angioplasty and acute myocardial infarction, i.e.        perithrombolysis. Agents commonly used for adjunctive therapy in        the treatment of thrombotic disorders can be used, for example        heparin and/or aspirin, just to mention a few.    -   xiv) providing for the use of the compounds of the invention for        a method of treating mammals to alleviate the pathological        effects of atherosclerosis and arteriosclerosis, acute MI,        chronic stable angina, unstable angina, transient ischemic        attacks and strokes, peripheral vascular disease, arterial        thrombosis, preeclampsia, embolism, restenosis or abrupt closure        following angioplasty, carotid endarterectomy, and anastomosis        of vascular grafts.    -   xv) providing for the use of the compounds of the invention for        the in vitro to inhibit the aggregation of platelets in blood        and blood products, e.g. for storage, or for ex vivo        manipulations such as in diagnostic or research use. This        invention also provides a method of inhibiting platelet        aggregation and clot formation in a mammal, especially a human,        which comprises the internal administration.    -   xvi) providing for the use of the compounds of the invention for        treatment of chronic or acute states of hyperaggregability, such        as disseminated intravascular coagulation (DIC), septicemia,        surgical or infectious shock, post-operative and post-partum        trauma, cardiopulmonary bypass surgery, incompatible blood        transfusion, abruptio placenta, thrombotic thrombocytopenic        purpura (TTP), snake venom and immune diseases, which are likely        to be responsive to these compounds.    -   xvii) providing for the use of the compounds of the invention in        a method for inhibiting the reocclusion of an artery or vein        following fibrinolytic therapy, which comprises internal        administration of compound and a fibrinolytic agent. When used        in the context of this invention, the term fibrinolytic agent is        intended to mean any compound, whether a natural or synthetic        product, which directly or indirectly causes the lysis of a        fibrin clot. Plasminogen activators are a well known group of        fibrinolytic agents. Useful plasminogen activators include, for        example, anistreplase, urokinase (UK), pro-urokinase (pUK),        streptokinase (SK), tissue plasminogen activator (tPA) and        mutants, or variants thereof, which retain plasminogen activator        activity, such as variants which have been chemically modified        or in which one or more amino acids have been added, deleted or        substituted or in which one or more functional domains have been        added, deleted or altered such as by combining the active site        of one plasminogen activator or fibrin binding domain of another        plasminogen activator or fibrin binding molecule.    -   xviii) providing for use of the compounds of the invention for        extracorporeal circulation, which is routinely used for        cardiovascular surgery in order to oxygenate blood. Platelets        adhere to surfaces of the extracorporeal circuit. Platelets        released from artificial surfaces show impaired hemostatic        function. Compounds of the invention can be administered to        prevent adhesion.    -   xix) providing for the use of the compounds of the invention for        other applications including prevention of platelet thrombosis,        thromboembolism and reocclusion during and after thrombolytic        therapy and prevention of platelet thrombosis, thromboembolism        and reocclusion after angioplasty of coronary and other arteries        and after coronary artery bypass procedures.

To achieve the above and other objects the present invention providesnovel pharmacologically active compounds, specifically new 2-alkyl arylsulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acidesters/amides which are used as potential therapeutic agents forintravascular thrombosis, myocardial ischemia and stroke and otherdisorders as mentioned above.

The compound of the invention has the formula 1

wherein R represents methyl ester or amide and R₁ represents alkyl, aryland heteroaryl moiety. Representative compounds include:

-   -   a. 2[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   b. 2[2,4,6, trimethyl benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   c. 2[2,nitrobenzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   d. 2[1-napthyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid ester    -   e. 2-4-metoxy benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3        ,4-b] indole-3-carboxylic acid ester    -   f. 2[8-quinoline sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid ester    -   g. 2-[ dansyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid ester    -   h. 2[2,4,6 tri isopropyl benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   i. 2[4-floro benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   j. 2[2-tri floro methyl benzene sulfonyl]-l,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   k. 2[methyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid ester    -   l. 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   m. 2[benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid ester    -   n. 2[4-methyl benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester    -   o. 2[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   p. 2[-4-methoxy benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   q. 2[-1-napthylsulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid amide    -   r. 2[8-quinoline sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]        indole-3-carboxylic acid amide    -   s. 2[-4-floro benzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   t. 2[methane sulphonyl sulfonyl-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   u. 2[3-nitro benzene sulfonyl-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   v. 2[2,4,6 trimethyl benzene sulfonyl-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide    -   w. 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide

In the specification in formula 1, R designates methylester and amide R₁designates alkyl group includes methyl, aryl group includes naphthyl andphenyl group substituted by alky, alkoxy, halogen groups and heteroarylgroup includes quinoline.

A preferred group of compound comprises those in which R=methylester/amide and R₁=methyl, benzene, 4-methyl benzene, 2-napthalene, 2,5dichlorobenzene, 2,4,6, trimethyl benzene, 2,nitrobenzene, 1-napthyl,4-metoxy benzene, 8-quinoline, dansyl, 2,4,6 tri isopropyl benzene,4-floro benzene, tri floro methyl benzene.

The invention also provides a pharmaceutical composition comprising acompound of formula 1 in a mixture with a pharmaceutically acceptableconventional carriers and a process for the preparation of apharmaceutical composition which comprises bringing a compound of theformula 1 into association with a pharmaceutically acceptableconventional carrier.

In addition, the invention provides a method of treating intravascularthrombosis and myocardial ischemia and stroke in mammals, that comprisesadministering to a subject in need thereof an effective amount of acompound of formula 1.

The compounds of the invention are useful in therapy, particularly inthe prevention of platelet aggregation. The compounds of the inventionhave shown to possess antithrombotic activity in different test models.The compounds of the present invention are thus useful asanti-thrombotic agents, and are thus useful in the treatment orprevention of unstable angina, coronary angioplasty and myocardialinfarction. The compounds prevent intravascular thrombosis, itsprogression or recurrence. They may be useful as additive or synergistictherapy to reduce the incidence of myocardial ischemia, acute myocardialinfarction, unstable angina, during and after angioplasty or stentreplacement, prevent cerebrovascular events, secondary prevention ofstroke and pulmonary thromboembolism. These agents may also be used incombination with antithrombotic drugs and anticoagulants in patientsundergoing angioplasty or stenting for coronary artery disease and alsoin conjunction with fibrinolysis protocols.

Diseases or conditions associated with platelet aggregation aredisorders or procedures characterized by thrombosis, primary arterialthrombotic complications of atherosclerotic disease, thromboticcomplications of interventions of atherosclerotic disease, thromboticcomplications of surgical or mechanical damage, mechanically-inducedplatelet activation, shunt occlusion, thrombosis secondary to vasculardamage and inflammation, indications with a diffuse thrombotic/plateletconsumption component, venous thrombosis, coronary arterial thrombosis,pathological effects of atherosclerosis and arteriosclerosis, plateletaggregation and clot formation in blood and blood products duringstorage, chronic or acute states of hyper-aggregability, reocclusion ofan artery or vein following fibrinolytic therapy, platelet adhesionassociated with extracorporeal circulation, thrombotic complicationsassociated with thrombolytic therapy, thrombotic complicationsassociated with coronary and other angioplasty, or thromboticcomplications associated with coronary artery bypass procedures.

Disorders or procedures associated with thrombosis are unstable angina,coronary angioplasty, or myocardial infarction; said primary arterialthrombotic complications of atherosclerosis are thrombotic stroke,peripheral vascular disease, or myocardial infarction withoutthrombolysis; said thrombotic complications of interventions ofatherosclerotic disease are angioplasty, endarterectomy, stentplacement, coronary or other vascular graft surgery; said thromboticcomplications of surgical or mechanical damage are associated withtissue salvage following surgical or accidental trauma, reconstructivesurgery including skin flaps, or reductive surgery; saidmechanically-induced platelet activation is caused by cardiopulmonarybypass resulting in microthromboembolism and storage of blood products;said shunt occlusion is renal dialysis and plasmapheresis; saidthromboses secondary to vascular damage and inflammation are vasculitis,arteritis, glomerulonephritis or organ graft rejection; said indicationswith a diff-use thrombotic/platelet consumption component aredisseminated intravascular coagulation, thrombotic thrombocytopenicpurpura, hemolytic uremic syndrome, heparin-induced thrombocytopenia, orpre-eclampsialeclampsia; said venous thrombosis are deep veinthrombosis, veno-occlusive disease, hematological conditions, ormigraine; and said coronary arterial thrombosis is associated withunstable angina, coronary angioplasty or acute myocardial infarction.

Pathological effects of atherosclerosis and arteriosclerosis arearteriosclerosis, acute myocardial infarction, chronic stable angina,unstable angina, transient ischemic attacks, strokes, peripheralvascular disease, arterial thrombosis, preeclampsia, embolism,restenosis or abrupt closure following angioplasty, carotidendarterectomy, or anastomosis of vascular grafts; said chronic or acutestates of hyper-aggregability is caused by DIC, septicemia, surgical orinfectious shock, post-operative trauma, post-partum trauma,cardiopulmonary bypass surgery, incompatible blood transfusion, abruptioplacenta, thrombotic thrombocytopenic purpura, snake venom or immunediseases. A method of preparation of the inventive compounds consists ofthe condensation of different alkyl/aryl sulphonyl chlorides with dlmethyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate/dl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide to get thecompounds of formula 1 (2-alkyl/aryl sulphonyl-1, 2, 3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters/amides)as shown in scheme 1 of the accompanying drawings.

The compounds of the present invention can be used as pharmaceuticalcompositions comprising compounds of the present invention with asuitable pharmaceutical career. Preferably, these compositions are usedto produce intravascular antithrombotic activity and contain aneffective amount of the compounds useful in the method of the invention.The most preferred compounds of the invention are

-   -   1. 2[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.    -   2. 2[-4-methoxy benzene sulfonyl]-1, 2, 3, 4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.    -   3. 2-[2-napthalene sulfonyl]-l, 2, 3, 4,-tetra        hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.

The reaction leading to 2-alkyl/aryl sulphonyl-1, 2, 3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters/amides isshown in scheme 1 which represents the reaction sequence resulting in2-alkyl aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indole-3-carboxylic acid esters/amides, according to the presentinvention.

It will be noted that according to the foregoing scheme the methods thatlead to the synthesis of 2-alkyl/aryl sulphonyl-1, 2, 3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters/amides offormula 1 as shown earlier are as follows

The method involves in the synthesis of the compounds of formula 1wherein R is methyl ester comprises of condensation of an alkyl or arylsulphonyl chloride with dimethyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylate of formula 2 in the presence of a baseselected from trimethylamine, potassium carbonate, pyridine in organicsolvent selected from THF, DMF, acetone, dioxane at a temperatureranging from 30° C. to 120° C. for 8 to 24 hours to produce thecorresponding 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid esters.

Two methods were used for the synthesis of 2-alkyl/aryl sulphonyl-1, 2,3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid amides.

The first method relates to a process for the synthesis of the abovecompounds by condensing a alkyl or aryl sulphonyl chloride with dli 1,2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide formula 3 in thepresence of a base selected from trimethylamine and an organic solventDMF at temperature 30° C. to 120° C. for 8 to 12 hours to produce thecorresponding 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid amide of formula 1 wherein R═CONH₂.

The second method involves 2-alkyl/aryl sulphonyl-1, 2, 3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esterssynthesized as described previously, treated with methanolic ammonia for24-32 hours at 32° C. to obtain 2-alkyl/aryl sulphonyl-1, 2, 3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid amide.

The compounds of the invention show marked antithrombotic activity andcan be used as therapeutic agents for the treatment of intravascularthrombosis, myocardial ischemia and stroke as shown for instance by thefollowing data of the compounds

-   (i) 2-[2,5-dichlorobenzene sulfonyl]-1,2,3,4,-tetra    hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester,-   (ii) 2-[4-methoxy benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3    ,4-b] indole-3-carboxylic acid amide.-   (iii) 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra    hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide,    Pharmacological Activity    (1) Methods:

1.1 Effect on mouse thrombosis: Pulmonary thromboembolism was induced byfollowing a method of Diminno and Silver ⁽¹⁾. Test compounds (30 μM/Kg)or vehicle were administered orally 60 min prior to the thromboticchallenge. A mixture of collagen (150 μg/ml) and adrenaline (50 μg/mL)was administered by the rapid intravenous injection into the tail veinto induce hind limb paralysis or death. A group of 10 animals were usedto evaluate the effect of test compound, while 5 mice were used toassess effect of a standard drug, aspirin and a group of vehicle treated(n=5) mice was also used in each experiment. % Protection was expressedas:$\frac{\left( {P_{control} - P_{test}} \right)}{P_{control}} \times 100$

P_(test) is the number of animals paralyzed/dead in the testcompound-treated group, and P_(contol) is the number of animalsparalyzed/dead in vehicle treated group.

1.2 Effect on mouse-tail bleeding time: Mice tail bleeding time wasperformed by method of Dejna et al, ⁽²⁾. The tail 2 mm from tip wasincised and the blood oozed was soaked with filter paper till thebleeding stops. The time elapsed from the tip incision to the stoppageof bleeding was determined as the bleeding time. Test compound (30μM/kg), aspirin or vehicle was given orally 60 min prior to the tailincision. Each group consisted of 5 mice.

1.3 Evaluation of compounds on platelet aggregation: Plateletaggregation was monitored according to the protocol described earlier⁽³⁾. Sprague Dawley rats (wt 250-300 gm) were anaesthetized with etherand blood (9 mL) was drawn from the heart into a plastic syringecontaining 1 ml of 1.9% tri-

Sodium citrate: The blood was centrifuged at 275×g for 20 min and theplatelet rich plasma (PRP) was collected. The remaining blood wasfurther centrifuged at 1500 g for 15 min at 20° C. to obtain plateletpoor plasma (PPP). The platelet count in the PRP was adjusted to 2×10⁸cells/ml by. using PPP. Adenosine-5′-diphosphate (ADP), thrombin,collagen, calcium ionophore A23187 or phorbol myristate ester (PMA)induced aggregation was monitored on a dual channel aggregometer(Chrono-log, USA). The test compound was incubated with PRP for 5 minbefore the addition of aggregation inducing agent. Percent inhibition ofthe test compounds at various concentrations was calculated as follows:${\%{\quad\quad}{Inhibition}} = {\frac{\left\lbrack {{Aggregation}_{vehicle} - {Aggregation}_{test}} \right\rbrack}{{Aggregation}_{vehicle}} \times 100}$

1.4 Evaluation of coagulation parameters: Blood was collected by cardiacpuncture from ether-anaesthetized rat using a syringe containing 3.2%tri-sodium citrate (9:1,v/v). Plasma was obtained by centrifugation ofcitrated blood at 2500×g for 15 min at 20° C. Stock solutions of thetest compounds were prepared freshly in DMSO and were diluted in DMSO.Thrombin time (TT), prothrombin time (PT) and activated partialthromboplastin time (aPTT) were evaluated according to manufacturer'sinstructions supplied with kits (Stago, France) and measured byCoagulometer (Stago, France) ⁽⁴⁾. In each set of experiment effect ofDMSO on these parameters was also assessed and was used to calculatechange in TT, PT or aPTT.

1.5 Rabbit venous thrombosis model: Experiments were performed on NewZealand white strain rabbits (2-3 kg) either sex. Escherichia coli LPSstrain 1055:B5 (Sigma Chemicals, USA) was injected intravenously via earvein (1 μg/kg) ^((5,6)). Jugular veins on both sides were exposed anddissected free from surrounding tissue. Two loose sutures were placed1.5 cm apart and all collateral veins were ligated. Four hours after E.Coli endotoxin injection (animal is watched for any signs ofhypersensitivity reaction during this period), stasis was establishedand maintained for 45 min by tightening the two sutures. Ligatedsegments were removed and opened longitudinally and the thrombus wascarefully removed and weighed. Heparin sodium (Beparine from beefintestinal mucosa ≧140 USP units/mg; Biological E. Limited, India) wasgiven in doses of (0.5, 0.25, 0.1 mg/kg i.v., via ear vein) 5 min beforestasis.

1.6 Effect of compound (i) on human platelet aggregation in vitro.:Platelet aggregation study was done on human platelets followingisolation of PRP from the human blood as described above (1.3).Aggregation was induced by collagen (10 μg/ml, 5 μg/ml), ADP (10 μM) andthrombin (0.5U/ml).

2. Results: Effect of test compounds is indicated in the following table(1) against collagen and epinephrine induced thrombosis in mice, whichis a primary screening model to detect antithrombotic efficacy of thetest agents. At the same dose these compounds were also evaluated fortheir effect on the bleeding time in mouse (Table 1).

Since compound (i), (ii) and (iii) exhibited significant protectionthese compounds were further analysed in greater details for theanti-thrombotic activity in various test systems, as indicated below.

Effect on venous thrombosis model in rabbit: The selected compounds wereevaluated at 10 μM/Kg and 30 μM/kg dose for their efficacy againststasis induced thrombosis in LPS treated rabbits. (i) was found to bemost effective as it inhibited thrombus formation significantly at both30 and 10 μM/Kg, while n and a inhibited thrombus formations only at 30μM/Kg. heparin was used as standard drug in this model and the resultsobtained are shown in the Table 2.

Ex vivo effect of selective compounds on rat platelet aggregation: Bloodwas collected in sodium citrate to obtain PRP and evaluate the ex vivoeffect of selective compounds ((i), (ii) ,(iii) at 30 μM/kg administeredby the ip route) against ADP, collagen, phorbol myristate ester (PMA)calcium ionophore (A23187), or thrombin induced aggregation. It wasobserved that all these compounds were consistent againstcollagen-induced platelet aggregation (Table 3). (iii) inhibited ADP(10μM), collagen (10 μg/ml), PMA (1.5 μM), and thrombin (0.64U/ml) inducedplatelet aggregation while no inhibition was found against calciumionophore A23187 (2.5 μg/ml) induced platelet aggregation. Compound (ii)inhibited only ADP (10 μM), collagen (10 μg/ml), PMA (1.5 μM), andA23187 (2.5 μg/ml) induced platelet aggregation however it did notinhibit thrombin (0.64U/ml) induced platelet aggregation. Compound(i)inhibited ADP (10 μM), collagen (10 μg/ml), and A23187 (2.5 μg/ml)induced platelet aggregation but had no inhibitory effect againstthrombin (0.64U/ml) and PMA (1.5 μM) induced platelet aggregation.

Effect on clotting parameters: The selected compounds were also testedin vitro for their effect on thrombin time (TT), prothrombin time (PT)and activated partial thromboplastin time (aPTT) at 100 μg/ml and 200μg/ml in vitro (Table 4). The test compounds at 100 μg/ml had nosignificant effect of on these parameters. Some effect was though seenon PT at 200 μg/ml concentration, but the concentration seems to bequite high.

Effect of compound(i) on human platelet aggregation in human PRP invitro: Since the compound(i) exhibited promising profile against venousthrombosis model in rabbits as well as in other test systems; it wastherefore further studied for inhibition of aggregation in humanplatelet rich plasma (PRP). It was found to be a competitive inhibitorof collagen induced platelet aggregation, collagen (10 μg/ml) inducedaggregation was not so significantly reduced in presence of compound(i),while response of low concentration of collagen (5 μg/ml) was reducedsignificantly (FIG. 1). TABLE 1 Antithrombotic Effect of the testcompounds on mice model and bleeding time Antithrombotic Sl Compound No.activity (AT) Bleeding time (BT) no. (dose 30 μM/kg) (% protection) %increase (1 hr) Control  0 — 1 A Compound(i) 60 ± 10 51 ± 14 (n = 4) (n= 5) 2 b 20 31 3 c  0 18 4 d 20 0 5 e  0 13 6 f 20 25 7 g 20 0 8 h  0 09 i  0 0 10 j 56 150 11 k 50 0 12 o 40 31 13 p Compound(ii) 70 ± 10 33 ±12 (n = 3) (n = 3) 14 q 20 12 15 r 30 0 16 s 60 13 17 t 30 0 18 u 45 019 v 30 50 20 w Compound(iii) 70 ± 0  61 ± 16 (n = 3) (n = 3) Aspirin(30 mg/Kg) 38 ± 3  125 ± 6  (n = 24) (n = 30) Indomethacin (10 mg/kg) 55± 15 — (n = 20)n = number of groups

Number of mice used for AT testing were 10 in each group, while 5 micewere used in each group to evaluate BT. Values are mean ±SEM TABLE 2Effect of Test compounds on venous thrombosis model in rabbits: TestThrombus % Thrombus % Thrombus compounds wt. Reduction wt. Reduction wt.% Reduction 10 μM/Kg dose 30 μM/Kg dose Control  43 ± 13 (i) 26 ± 0 410.0 ± 0.0 100.0 (ii) 79 ± 9 −67  5 ± 4 88 (iii) — — 11 ± 5  57 0.5 mg/Kgdose 0.25 mg/kg dose 0.1 mg/Kg dose Heparin   1 ± 0.2 98   2 ± 0.3 95 4± 0.5 91Values are Mean ± ;,Compound (i); n = 2, Compound (ii); n = 4, Compound (iii); n = 4 [n isno. pf observations in 2 or more animals at 10 μM/Kg or 30 μM/Kg p.o.administered 2 h prior to the stasis] or vehicle control [n = 10observations in five animals]. In heparin treated group n = 6observations for each dose in nine animals.

TABLE 3 Effect of Test compounds on the platelet aggregation Compound(i)Compound(ii) Compound(iii) Aggregation % % % % % % Inducers AggregationInhibition Aggregation Inhibition Aggregation Inhibition ADP 37 ± 4  17± 6 35 ± 5 26 ± 10   2 ± 0.4  94 ± 0.2 (10 μM) n = 12 n = 12 n = 8 n = 8n = 4 n = 4 Thrombin 45 ± 4  −9 ± 9 44 ± 10  4 ± 10  28 ± 3  40 ± 6(0.64 U/ml) n = 10 n = 10 n = 4 n = 4 n = 6 n = 6 Collagen 22 ± 9  65 ±13  5 ± 1 79 ± 7 2.5 ± 0  47 ± 13 (10 μg/ml) n = 8 n = 8 n = 4 n = 4 n =2 n = 2 A23187 51 ± 4  11 ± 4 51 ± 5 54 ± 4  57 ± 6 −25 ± 2 (2.5 μg/ml)n = 8 n = 8 n = 6 n = 6 n = 4 n = 4 PMA 58 ± 6 −12 ± 9 44 ± 12 26 ± 0.3 38 ± 13  32 ± 5 (1.5 μM) n = 6 n = 6 n = 2 n = 2 n = 2 n = 2n = number of experiments which consists of at least 6 or moreobservations

TABLE 4 Effect of test substances against clotting parameters CompoundCompound (i) Compound (ii) Compound (iii) Conc. (μg/ml) % ChangeThrombin time (TT) 5 ± 5  9 ± 5 10 ± 4  100 9 ± 5  9 ± 4 6 ± 1 200Prothrombin time (PT) 19 ± 16  9 ± 5 −0.24 ± 0.8    100 14 ± 3  14 ± 7  9 ± 0.2 200 Activated partial 7 ± 5 13 ± 7 11 ± 4  100 thromboplastintime 4 ± 3 11 ± 4 10 ± 8  200 (aPTT)Values are mean ± SEM (number of observation [n] = 3 in each case)

The following examples are provided by the way of illustration of thepresent invention.

EXAMPLE 1 Preparation of 2-[-2,5 dichlorobenzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester.

i) 2,5 dichlorobenzene sulphonyl chloride (0.541 gm, 2.2 mmol) in dryacetone (5 ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,2.0mmol)and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8 ml)during 15 min and was allowed to stirr for 10 hrs. at roomtemperature(32° C.). The reaction mixture was concentrated under vaccum,the residue was triturated with water (20 ml) to get2-[2,5-dichlorobenzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester, crystallized with methanol, Yield=0.650gm(74.03%). m.p.=205° C. Mass (FAB) m/z =440 (M⁺). IR(KBr cm⁻¹): 3412,1730, 1600, 1446, 1343, 1271, 1162, 738. H¹NMR (200 MHz, CDCl₃): δ3.14-3.38 (m,2H), δ 3.61(s,3H), δ4.67-4.88 (m,2H), δ5.19 (d,1H), δ7.08-7.21 (m,2H), δ7.44-7.49 (m,3H), δ7.79(d, 1H)δ 8.16 (s,1H).Molecular Formula=C₁₉H₁₆Cl₂N₂O₄S.

EXAMPLE 2 Preparation of 2-[2,4,6, trimethylbenzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester.

i) 2,4,6, trimethyl benzene sulphonyl chloride (0.479 gm,2.2 mmol) indry acetone (5 ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,2.0 mmol)and dry triethylamine (0.56 ml ,4.0 mmol) in dry acetone (8 ml)during 15min and was allowed to stirr for 8 hrs. at room temperature (32° C.).The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[2,4,6, trimethyl benzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester, crystallized with methanol, Yield=0.521 gm(63.21%). m.p.=160° C.Mass (FAB) m/z=413 (M⁺). IR(KBr cm⁻¹): 3400, 2938, 1734, 1599, 1452,1330, 1237, 1153, 738. ¹HNMR (200 MHz, CDCl₃): δ 2.29(s,3H),δ2.63(s,6H), δ3.05-3.39 (m,2H), δ3.64 (s,3H), δ4.50(d,1H), δ 4.79-4.93(m,2H), δ6.95(s, 2H)δ7.05-7.20 (m,2H), δ7.45(d,1H), δ7.78 (s,3H).Molecular Formula=C₂₂H₂₄N₂O₄S.

EXAMPLE 3 Preparation of 2[2, nitrobenzenesulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester.

i) 2-nitrobenzenesulphonyl chloride (0.486 gm, 2.2 mmol) in dry acetone(5 ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm, 2 mmol)and dry triethylamine (0.56 ml,4.0 mmol) in dry acetone (8 ml) during15 min and was allowed to stirr for 8 hours at room temperature(32° C.).The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[2,nitrobenzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester, crystallized with methanol, Yield=0.42 gm (50.6% ), m.p.=225-230°C. Mass (FAB) m/z=416 (M⁺). IR (KBr cm⁻¹): 3424, 1743, 1598, 1363, 1229,1166,753. ¹HNMR (200 MHz, CDCl₃): δ 3.16-3.44(m,2H), δ3.55 (s, 3H),δ4.83 (s,2H), δ5.20 ( d ,1H), δ 7.04-7.19 (m,2H), δ 7.33(d,1H), δ7.45-7.47 (m, 1H) δ7.69-7.79 ( m,3H), δ 8.10-8.18(m,1H). MolecularFormula=C₁₉H₁₇N₃O₆S.

EXAMPLE 4 Preparation of 2[1-napthyl sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester.

i) 1-napthylsulphonyl chloride (0.497 gm, 2.2 mmol) in dry acetone (5ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm, 2.0 mmol)and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8 ml)during 15min and was allowed to stirr for 8 hrs. at room temperature(32° C.). Thereaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[1-napthylsulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester, crystallized with methanol, Yield=0.55 gm (65%), m.p.=215° C.Mass (FAB) m/z=421 (M⁺). IR (KBr cm⁻¹):3402, 1736,, 1596, 1447, 1325,1236, 1200, 1163, 733. ¹HNMR (200 MHz, CDCl₃): δ3.09-3.29(m,1H),δ3.35-3.40(m,4H), δ4.76(s,2H), δ5.28(d,1H,),δ7.03-7.19(m,2H),δ7.40-7.70(m,5H), δ7.90(d,1H), δ8.06 (d,1H), δ8.30(d,1H), δ8.68 (d,1H). Molecular Formula=C₂₃H₂₀N₂ 0 ₄S.

EXAMPLE 5 Preparation of 2-[4-methoxy benzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester.

i) 4-methoxy benzene sulphonyl chloride (0.453 gm, 2.2 mmol) in dryacetone (5 ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm, 2.0 mmol)and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8 ml) during15 min and was allowed to stirr for 8 hours at room temperature (32°C.). The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[4-methoxy benzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester, crystallized with methanol, Yield=0.682 gm (85.25%) m.p.=215° C.Mass (FAB) m/z=401 (M⁺). IR (KBr cm⁻¹) 3426,1748 , 1594, , 1450, 1344,1256, 1155, 741. ¹HNMR (200 MHz, CDCl₃): δ3.05-3.37(m,2H), δ3.47(s,3H),δ3.84 (s,3H), δ4.59-4.86(m,2H) δ5.16(d,1H,), δ6.92-7.46(m,5H), δ7.82(d,3H). Molecular Formula=C₂₀H₂₀N₂O₅S.

EXAMPLE 6 Preparation of 2-[8-quinoline sulfonyl]-1, 2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.

i) 8-quinolinesulphonyl chloride (0.499 gm, 2.2 mmol) in dry acetone (5ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,2.0 mmol)and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8 ml) during15 min and was allowed to stirr for 8 hours. at room temperature(32°C.). The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[8-quinolinesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester, crystallized with methanol, Yield=0.619 gm ( 73.6%) , m.p.=235°C.Mass (FAB) m/z=422 (M⁺).IR (KBr cm⁻¹) 3400, , 1733, 1621,1564, 1446,1327, 1213, 1161, 743. ¹HNMR(200 MHz, CDCl₃): δ2.99-3.10( m,1H),δ3.31-3.44(m, 4H), δ4.80-5.01 (m, 2H), δ5.78 (d ,1H), δ7.00-7.18 (m,2H), δ7.39-7.49(m, 2H), δ7.60-δ7.80 (m, 2H), δ8.02(d,1H), δ8.20 (d,1H),δ8.56 (d, 1H), δ9.00(d, 1H). Molecular Formula=C₂₂H₁₉N₃O₄S.

EXAMPLE 7 Preparation of 2-[dansyl sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.

i) 2-dansyl sulphonyl chloride (0.592 gm,2.2 mmol) in dry acetone (5 ml)was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,2.0 mmol)and dry triethylamine (0.56 ml ,4.0 mmol) in dry acetone (8 ml) during15 min and was allowed to stirr for 8 hrs. at room temperature(32° C.).The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[dansyl sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester,crystallized withacetone, Yield=0.364 gm(44.9%) m.p.=195° C. Mass (FAB) m/z=464 (M⁺).IR(KBr cm⁻¹): 3407, 1741, 1595, 1451, 1345, 1201,1151,744. ¹HNMR (200MHz, CDCl₃) δ2.85 (s,6H),δ3.08-3.18(m,1H),δ3.33-3.45 (m,4H),δ4.71-4.77(m,2H),δ5.28 (d,1H), δ7.10-7.16 (m,3H),δ7.39-7.58 (m,3H),δ7.75 (s,1H),δ8.29 (d,2H),δ8.51 (d,1H). Molecular Formula=C₂₅H₂₅N₃O₄S.

EXAMPLE 8 Preparation of 2-[2,4,6 tri isopropyl benzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester.

i) 2,4,6 tri isopropyl benzene sulphonyl chloride (0.664 gm,2.2 mmol) indry acetone (5 ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,2.0 mmol)and dry triethylamine (0.56 ml ,4.0 mmol) in dry acetone (8 ml) during15 min and was allowed to stirr for 24 hrs. at room temperature(32° C.).The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[2,4,6 tri isopropyl benzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester, crystallized with acetone, Yield=0.310 gm (31.25%) m.p.=200° C.Mass (FAB) m/z=497 (M⁺). IR (KBr cm⁻¹): 3408, 2960,1744, 1626, 1457,1317, 1160, 1040, 934, 746. ¹HNMR (200 MHz, CDCl₃) δ1.20-1.33(m,18H),δ2.81-2.98(m,1H), δ3.10-3.40(m,2H), δ3.65(s,3H), δ4.05-4.19(m,2H),δ4.45(d,1H), δ4.88(d,1H), δ5.12 (d,1H), δ7.05-7.17(m,4H), δ7.46 (d,1H),δ7.80 (s,1H). Molecular Formula=C₂₈H₃₆N₂O₄S.

EXAMPLE 9 Preparation of 2-[4-floro benzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.

i) 4-floro benzene sulphonyl chloride (0.427 gm,2.2 mmol) in dry acetone(5 ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,2.0 mmol)and dry triethylamine (0.56 ml ,4.0 mmol) in dry acetone (8 ml) during15 min and was allowed to stirr for 8 hrs. at room temperature(32° C.).The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[4-floro benzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester, crystallized with acetone, Yield=0.666 gm (67.19%) m.p.=190° C.Mass (FAB) m/z=389 (M⁺). IR(KBr cm⁻¹) 3430,1748, 1591,1489,1344, 1228,1156,742. ¹ HNMR (200 MHz, CDCl₃) δ3.08-3.19 (m, 1H), δ3.32-3.47(m, 4H),δ4.59-4.88(m,2H), δ5.16 (d,1H), δ7.10-7.32(m,4H), δ7.45 (d,1H),δ7.83-7.90-(m,3H). Molecular Formula=C₁₉H₁₇FN₂O₄S.

EXAMPLE 10 Preparation of 2-[2-tri floro methyl benzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester.

i) 2-tri floro methyl benzene sulphonyl chloride (0.537 gm, 2.2 mmol) indry acetone (5 ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm, 2.0 mmol)and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8 ml) during15 min and was allowed to stirr for 8 hrs. at room temperature(32° C.).The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[2-tri floro methyl benzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester., crystallized with acetone, Yield=0.524 gm (59.8%), m.p.=136° C.Mass (FAB) m/z=439 (M⁺)

IR (KBr cm⁻¹) 3400, 1741, 1563, 1449, 1347, 1308, 1272, 1218, 1169, 771.¹HNMR (200 MHz, CDCl₃): δ3.18-3.24 (m,1H), δ3.40-3.50(m,1H),δ3.56(s,3H,), δ4.75 (s,2H), δ5.20 (d,1H), δ7.11-7.15 (m,2H),δ7.46-7.49(d,1H), δ7.68-7.91-(m,4H), δ8.21-8.24(m, 1H). MolecularFormula=C₂₀H₁₇F₃N₂O₄S.

EXAMPLE 11 Preparation of 2-[methane sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.

i) Methane sulphonyl chloride (0.18 ml,2:4 mmol) in dry acetone (5 ml)was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm, 2.0 mmol)and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8 ml) during15 min and was allowed to stirr for 8 hrs. at room temperature(32° C.).The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[methyl sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, crystallized withacetone. Yield=0.480 gm (77.9%), m.p.=198° C. Mass (FAB) m/z=309 (M⁺).IR (KBr cm⁻¹),3384, 3026, 1736, 1632, 1278, 1234, 1152, 1016, 746. ¹HNMR(200 MHz, Acetone): δ2.91(s.3H),δ2.97-3.35(m, 2H),δ3.51(s,3H),δ4.52-4.74(m,2H),δ4.99 (d,1H), δ6.85-7.00(m,2H), δ7.22(d,1H), δ7.34 (d,1H), δ10.00(s,1H). Molecular Formula=C₁₄H₁₆N₂O₄S.

EXAMPLE 12 Preparation of 2-[2-napthalene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.

i) 2-naphthyl sulphonyl chloride (0.497 gm, 2.2 mmol) in dry acetone (5ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,2.0 mmol )and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (10 ml) during15 min and was allowed to stirr for 12 hours at room temperature 32° C.The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to give 2-[2-napthalenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester, crystallized with methanol, Yield=0.714 gm (85%). m.p-210° C.Mass (FAB) m/z=421 (M⁺). IR(KBr cm⁻¹): 3418, 1748, 1594, 1451, 1362,1158, 751. H¹NMR (200 MHz, CDCl₃): δ3.08-3.36(m, 5H), δ4.68-4.95 (m,2H),δ5.24 (d,1H), δ7.057.18 (m,2H), δ7.42(d,1H), δ7.60-7.63(m,2H),δ7.77-7.98 (m,5H), δ8.45 (s,1H). Molecular Formula=C₂₃H₂₀N₂ 0 ₄S.

ii) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in dry acetone (3ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23 gm, 1.0 mmol)and dry pyridine (0.97 ml, 1.2 mmol) in dry acetone (10 ml) during 15min and was allowed to stirr for 12 hours at room temperature(32° C.).The reaction mixture was concentrated under vaccum, water(10 ml) wasadded to the residue and extracted with chloroform (3×10 ml).The extractwas dried over Na₂SO₄ and concentrated over reduced pressure to give2-[2-napthalene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester, crystallized with methanol, Yield=0.227gm (54%), m.p-210° C.

iii) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in dry acetone(3 ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23 gm, 1.0 mmol)and K₂CO₃ (0.13 gm, 1.2 mmol) in dry acetone (10 ml) during 15 min andwas allowed to stirr for 8 hrs. at room temperature(32° C.). Thereaction mixture was concentrated under vaccum, water(10 ml) was addedto the residue and extracted with chloroform (3×10 ml).The extract wasdried over Na₂SO₄ and concentrated over reduced pressure to give2-[2-napthalene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester, crystallized with methanol, Yield=0.29gm.(68%) m.p-210° C.

iv) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in dry acetone (3ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23 gm, 1.0 mmol)and dry triethylamine (0.12 ml, 1.2 mmol) in TBF (5 ml) during 15 minand was allowed to stirr for 8 hours at room temperature(32° C.). Thereaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get obtain 2-[2-napthalenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester, crystallized with methanol, Yield=0.32 gm.( 75% ), m.p-210° C.

v) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in dry acetone (3ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23 gm, 1.0 mmol)and dry triethylamine (0.12 ml, 1.2 mmol) in DMF (3 ml) during 15 minand was allowed to stirr for 8 hrs. at room temperature(32° C.). Thereaction mixture was concentrated under vaccum, the residue wastriturated with water (10 ml) then extracted with chloroform (3×10ml).The extract was dried over Na₂SO₄ and concentrated over reducedpressure to give 2-[2-napthalene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester to get obtain2-[2-napthalene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester, crystallized with methanol, Yield=0.21gm. (50%), m.p-210° C.

vi) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in dry acetone (3ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate 0.23 gm, 1.0 mmol)and dry triethylamine (0.12 ml, 1.2 mmol) dry dioxane (5 ml) during 15min and was allowed to stirr for 8 hours at room temperature(32° C.).Water(10 ml) was added to the residue and extracted with chloroform(3×10 ml).The extract was dried over Na₂SO₄ and concentrated overreduced pressure to give 2-[2-napthalene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, crystallized withmethanol, Yield=0.29 gm.( 70%), m.p-210° C.

vii) 2-naphthyl sulphonyl chloride (0.272 gm,1.2 mmol) in dry THF (3 ml)was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23 gm, 1.0 mmol)and backed K₂CO₃ (0.13 gm, 1.2 mmol) in dry THF and was allowed to stirrfor 12 hours at 80° C. temperature. The reaction mixture wasconcentrated under vaccur, water(8 ml) was added to the residue andextracted with chloroform (3×5 ml).The extract was dried over Na₂SO₄ andconcentrated over reduced pressure to give 2-[2-napthalenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester which was purified by column chromatography over silica gel usingmethanol chloroform as eluent Yield=0.20 gm (48%), m.p-210° C.

viii) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in dry DMF (3ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23 g,, 1.0 mmol)and backed K₂CO₃ (0.13 gm, 1.2 mmol) in dry DMF and was allowed to stirrfor 8 hours at 120° C. temperature. The reaction mixture wasconcentrated under vaccum, water(8 ml) was added to the residue andextracted with chloroform (3×8 ml).The extract was dried over Na₂SO₄ andconcentrated over reduced pressure to give 2-[2-napthalenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidester which was purified by column chromatography over silica gel usingmethanol chloroform as eluent. Yield=0. 170 gm (40%), m.p-210° C.

EXAMPLE 13 [benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester

i) Benzene sulphonyl chloride (0.388 gm, 2.2 mmol) in dry acetone (5 ml)was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm, 2.0 mmol)and dry triethylamine (0.56. ml, 4.0 mmol) in dry acetone (8 ml) during15 min and was allowed to stirr for 8 hrs. at room temperature(32° C.).The reaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[benzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, crystallized withacetone. Yield=0.371 gm (50%), m.p.=124° C. Mass (FAB) m/z=371 (M⁺). IR(KBr cm⁻¹) : 3838, 3024, 1742, 1442, 1342, 1052, 746. ¹HNMR (200 MHz,CDCl₃): δ3.04-3.42(m, 5H), δ3.30-3.42(m,4H), δ4.61-4.89(m, 2H), δ5.16(d,1H), δ7.05-7.19(m,2H), δ7.42-7.60(m,4H), δ7.83-7.91(m, 3H). MolecularFormula=C₁₉H₁₈N₂O₄S.

EXAMPLE 14 2-[4-methyl benzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester

i) 4-methyl benzene sulphonyl chloride (0.419 gm, 2.2 mmol) in dryacetone (5 ml) was added to a stirred solution of dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm, 2.0 mmol)and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8 ml)during 15min and was allowed to stirr for 8 hrs. at room temperature(32° C.). Thereaction mixture was concentrated under vaccum, the residue wastriturated with water (20 ml) to get 2-[4-methyl benzenesulphonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylicacid ester, crystallized with acetone. Yield=0.400 gm (51%), m.p.=128°C. Mass (FAB) m/z=385 (M⁺). IR (KBr cm⁻¹): 3427, 1744, 1597, 1445, 1337,1159, 1091, 1051, 1016, 935, 746. ¹HNMR (200 MHz, CDCl₃): δ2.40(s, 3H),δ3.05-3.45(m,5H), δ4.60-4.87(m,2H), δ5.15(d,1H), δ6.96-7.46(m, 5H),δ7.70-7.85(m,3H). Molecular Formula=C₂₀H₂₀N₂O₄S.

EXAMPLE 15 Preparation of 2-[2,5 dichlorobenzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidamide.

i) 2,5 dichlorobenzene benzene sulphonyl chloride (0.590 gm, 2.4 mmol)in dry acetone(5 ml) was added to a stirred solution of dl 1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide (0.430 gm, 1.0 mmol) anddry triethylamine (0.56 ml, 4.0 mmol) in dry DMF(5 ml)during 15 min andwas allowed to stirr for 8 hrs. at room temperature(32° C.). Water wasadded to the reaction mixture and triturated to give 2-[2,5dichlorobenzene benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide which was purified by columnchromatography over silica gel using 2% methanol chloroform as eluent.Yield=0.400 gm (47.17%)

ii) 2-[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester (0.220 gm, 0.5mmol)was kept at room temperature (32° C.) in methanolic ammonia(25 ml)for 32 hours The reaction mixture was then evaporated under vaccum toobtain to obtain 2-[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide, crystallized inmethanol chloroform solution(2:1) Yield=0.185 gm (87.26%). m.p.=220° C.Mass (FAB) m/z=425(M⁺). IR (KBr cm⁻¹): 3456, 3332, 1693, 1602, 1450,1337, 1160, 752. H¹NMR (200 MHz, Acetone) δ3.06-3.73 (m, 2H), δ4.87(s,2H), δ4.97(d, 1H), δ6.41(s, 1H), δ7.01-6.84(m, 3H), δ7.32-7.21(m, 21H),δ7.60-7.48(m, 2H), δ8.08-8.67(d,1H), 67 9.95(s,1H). MolecularFormula=C₁₈H₁₅Cl₂N₃O₃S.

EXAMPLE 16 Preparation of 2-[4-methoxy benzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.

i) 4-methoxy benzene sulphonyl chloride (495 gm,2.4 mmol) in dryacetone(5 ml) was added to a stirred solution of dl 1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide (0.430 gm, 1.0 mmol) anddry triethylamine (0.56 ml, 4.0 mmol) in dry DMF(5 ml)during 15 min andwas allowed to stirr for 8 hrs. at room temperature(32° C.). Water wasadded to the reaction mixture and triturated to give 2-[4-methoxybenzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide,which was purified by columnchromatography over silica gel using 2% methanol chloroform as eluent.Yield=0.480 gm (62.34%). imp. =178-180° C.

ii) 2-[4-methoxy benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester (0.200 gm,0.5 mmol)was kept at roomtemperature(32° C.) in methanolic ammonia (30 ml) for 24 hrs. Thereaction mixture was then evaporated under vaccum to obtain 2-[4-methoxybenzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide, crystallized in methanol (5 ml)Yield=0.170 gm (88%), m.p.=178-180° C. Mass (FAB) m/z=386 (M⁺). IR(KBrcm¹): 3375, 1698, 1595, 1495, 1447, 1342, 1256, 1151, 756. H¹NMR (200MHz, CDCl₃) δ2.43-2.54(m, 1H), δ3.43-3.77(s,4H), δ4.80-4.96(m, 3H),δ6.81-6.86(d, 2H), δ7.04-7.39(m,6H), δ7.67-7.72(d,2H). MolecularFormula=C₁₉H₁₉N₃O₄S.

EXAMPLE 17 Preparation of 2-[1-napthyl sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.

i) 2-[1-napthylsulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester (0.210 gm, 0.5 mmol) was kept at roomtemperature (32° C.) in methanolic ammonia(30 ml) for 24 hrs. Thereaction mixture was then evaporated under vaccum to obtain2[-1-napthylsulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide, Yield=0.174 gm (85.7%). m.p.=145-150° C.Mass (FAB) m/z=406 (M⁺). IR (KBr cm⁻¹) 3397, ,1597, ,1447, 1349, 1204,1160, 799, 750. H¹NMR(200 MHz, CDCl₃): δ2.60-2.72 (m ,1H,), δ3.56(d,1H), δ4.60-5.00 (m,3H), δ5.39(s,1H), δ6.61(s,1H), δ7.03-7.49 (m ,7H),δ7.88(d,1H), δ8.06 (d,1H), δ8.30(d,1H), δ8.50(d,1H). MolecularFormula=C₂₂H₁₉N₃O₃S.

EXAMPLE 18 Preparation of 2-[8-quinoline sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.

i) 2-[8-quinoline sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester (0.211 gm, 0.5 mmol) was kept at roomtemperature(32° C.) in methanolic ammonia(30 ml) for 48 hrs The reactionmixture was then evaporated under vaccum to obtain 2-[8-quinolinesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidamide . This was purified by column chromatography over silica gel using2% methanol chloroform as eluent. Yield=0.130 gm (64.04%). m.p.=160° C.Mass (FAB) m/z=407(M⁺). IR (KBr cm⁻¹): 3426, 3338, 1686, 1617, 1493,1450, 1328, 1161, 1139, 740. H¹NMR(200 MHz, CDCl₃) δ2.33-2.45(m,1H),δ3.33-3.59(m,1H), δ5.16-5.48(m,3H), δ6.96-7.42(m,6H), δ7,61-7.83(m,2H),δ8.18-8.63(m,2H), δ8.56(d,1H), δ8.80-8.32(d,1H). MolecularFormula=C₂₁H₁₈N₄O₃S.

EXAMPLE 19 Preparation of 2-[4-floro benzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.

i) 2-[4-floro benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester (0.388 gm, 0.5 mol)was kept at roomtemperature(32° C.) in methanolic ammonia (30 ml)for 24 hrs The reactionmixture was then evaporated under vaccum to obtain 2-[4-floro benzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidamide Yield=0.300 gm(80.41%). m.p.=220° C.

Mass (FAB) m/z=374 (M⁺). IR (KBr cm⁻¹): 3461, 3371, 1690, 1598, 1488,1454, 1330, 1167, 764. H¹NMR (200 MHz, MeOH) δ2.69-2.80(m,1H) ,δ2.86-2.99(m,1H), δ4.66-5.05(m,3H), δ6.89-7.07(m,2H), δ7.14-7.3 1(m,5H),δ7.85-7.98(m,3H). Molecular Formula=C₁₈H₁₆FN₃O₃S.

EXAMPLE 20 Preparation of 2-[ methane sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.

i) Methane sulphonyl chloride (0.18 ml,2.4 mmol) was added to a stirredsolution of dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide(0.430 gm,2.0 mmol) and dry triethylamine (0.56 ml ,4.0 mmol) in dry DMF(8 ml) during 15 min at room temperature 30° C. The reaction mixture wasallowed to stirr for 8 hrs. at room temperature. Water(20 ml) was addedto the reaction mixture and extracted with chloroform(3×15 ml).Theextract was dried over Na₂SO₄ and concentrated over reduced pressure togive 2-[methane sulphonyl ]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide which was purified by columnchromatography over silica gel using 2% methanol chloroform as eluent.Yield=0.150 gm(25.60%). m.p.=234° C. Mass (FAB) m/z=294 (M⁺). IR(KBrcm⁻¹): 3483, 3361, 1685, 1610, 1446, 1325, 1148, 756. H¹NMR (200 MHz,CDCl₃) δ3.04(s,3H), δ3.20-3.63(m,2H), δ4.69-4.84(m,3H),δ6.96-7.15(m,3H), δ7.32-7.53(m,3H), δ10.89(s,1H). MolecularFormula=C₁₃H₁₅N₃O₃S.

EXAMPLE 2 Preparation of 2-[3-nitro benzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.

i) 3-nitro benzene sulphonyl chloride (0.531 gm,2.4 mmol) in dry acetonewas added to a stirred solution of dl 1, 2, 3, 4-tetrahydro-9H-pyrido(3, 4-b) indole-3-amide (0.430 gm,2.0 mmol) and dry triethylamine (0.56ml, 4.0 mmol) in dry DMF (8 ml) during 15 min and was allowed to stirrfor 8 hrs. at room temperature. The reaction mixture was allowed tostirr for 8 hrs. at room temperature. Water(20 ml) was added to thereaction mixture and extracted with chloroform(3×15 ml).The extract wasdried over Na₂SO₄ and concentrated over reduced pressure to give2-[3-nitro benzene sulfonyl-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide which was purified by columnchromatography over silica gel using 2% methanol chloroform as eluent.Yield=0.400 gm(50%). m.p.=252° C. Mass (FAB) m/z=401 (M⁺). IR(KBr cm⁻¹):3459, 3378, 1692, 1618, 1528, 1353, 1173, 760. H¹NMR(200MHz,CDCl₃+DMSOd₆): δ2.88(m,1H), δ3.33(d,1H), δ4.73(d,1H), δ4.93(d,1H),δ5.06(d,1H), δ6.41(s,1H), δ6.89-7.31(m,3H), δ7.63-7.71(m,3H),δ8.13-8.17(d, 1H), δ8.30 (d,1H), δ8.59 (d,1H), δ10.27(s, 1H). MolecularFormula=C₁₈H₁₆N₄O₅S.

EXAMPLE 22 Preparation of 2-[2, 4, 6 trimethyl benzenesulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidamide.

i) 2,4,6 trimethyl benzene sulphonyl chloride (0.524 gm,2.4 mmol) in dryacetone was added to a stirred solution of dl 1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide (0.430 gm,2.0 mmol) anddry triethylamine (0.56 ml, 4.0 mmol) in dry DMF (8 ml) during 15 minand was allowed to stirr for 8 hrs. at room temperature. Water (20 ml)was added to the reaction mixture and extracted with chloroform(3×15ml). The extract was dried over Na₂SO₄ and concentrated over reducedpressure to give 2-[2,4,6 trimethyl benzene sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide which was purifiedby column chromatography over silica gel using 2% methanol chloroform aseluent Yield=0.35 gm(44.08%) m.p.=212° C. Mass (FAB) m/z=398 (M⁺).IR(KBr cm⁻¹): 3394, 3299, 1668, 1596, 1455, 1324, 115.5, 752. H¹NMR (200MHz, DMSO d6) δ2.30(s,3H), δ2.56-2.74(m,7H), δ3.55-3.62(d,1H),δ4.49-4.70(m,3H), δ5.17(s,1H), δ5.49(s,1H), δ6.96-7.77(m, 6H). MolecularFormula=C₂₁H₂₃N₃O₃S.

EXAMPLE 23 Preparation of 2-[2-napthyl sulfonyl]-1,2,3,4,-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.

i) 2-[2-napthyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester (0.210 gm, 0.5 mol)was kept at roomtemperature(32° C.) in methanolic ammonia (30 ml)for 24 hrs The reactionmixture was then evaporated under vaccum to obtain 2-[2-napthylsulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acidamide Yield=0.142 gm(70%). m.p.=240° C. Mass (FAB) m/z=406 (M⁺). IR (KBrcm⁻¹): 3489, 3372, 1694, 1604, 1444, 1328, 1160, 1078, 754. H¹NMR (200MHz, Acetone): δ3.17-3.28(m,2H), δ4.67-4.99(m,3H), δ6.35(s,1H),δ6.76-6.91(m,3H), δ7.11-7.16(d,2H), δ7.48-7.55(m, 2H). δ7.67-7.97(m,4H), δ8.40(s,1H), δ9.86(s,1H). Molecular Formula=C₂₂H₁₉N₃O₃S.

REFERENCES

1. Diminno, G.; Silver, M. J. J. Pharmacol. Exp. Ther. 1983, 225, 57-60.

2. Dejna, E.; Collioni, A.; Quntana, A. Thromb. Res. 1979, 15, 191-197.

3. Dikshit, M.; Kumari, R.; Srimal, R. C. J. Pharmacol. Exp. Ther. 1993,265, 1369-1373.

4. S. Batra, S.; Roy, A. K.; Patra, A.; Bhaduri, A. P.; Surin, W. R.;Raghavan, S. A. V.; Sharma, P.; Kapoor, K.; Dikshit, M. Bioorg. Med.Chem. 2004, 12, 2059-2077.

5. Berry, C. N.; Girard, D.; Girardot, C.; Lochot, S.; Lunven, C.;Visconte, C. S. Thromb. Haemost. 1996, 22, 233-241.

6. Herbert, J. M.; Bernat, A.; Dol, F.; Herault, J. P.; Crepon, B.;Lormeau, J. M. J. Pharmacol. Exp. Ther. 1996, 276, 1030-1038.

1. A process for the preparation of a 2-alkyl/arylsulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acidester of formula I

wherein R is selected from methyl ester and amide; and R₁ is selectedfrom the group consisting of alkyl, aryl, and heteroaryl moiety, theprocess comprising condensing an alkyl or aryl sulphonyl chloride withdimethyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylateof formula 2

in the presence of a base and an organic solvent to obtain acorresponding 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido(3,4-b) indo.le-3-carboxylic acid ester of formula
 1. 2. A method asclaimed in claim 1 wherein the aryl is selected from the groupconsisting of substituted phenyl substituted by hydrogen, halogen, alkylor alkoxy, sunstituted napthyl substituted by hydrogen or dimethylamino; and heteroaryl.
 3. A method as claimed in claim 2 wherein theheteraryl is quinoline.
 4. A method as claimed in claim 1 wherein thereaction is carried out at a temperature in the range of 30° C. to 120°C. and for 8 to 24 hours.
 5. A method as claimed in claim 2 wherein thehalogen is selected from the group consisting of chlorine, brominefluorine, iodine, and mixtures thereof; alkoxy is selected from thegroup consisting of C₁-C₁₀ oxy; alkyl is selected from the groupconsisting of C₁-C₁₀ alkyl, and heteroaryl is selected from the groupconsisting of C₄-C₁₀ heteroaryl.
 6. A method for the preparation of2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indole-3-carboxylic acid amide of formula I

wherein R is selected from methyl ester and amide; and R₁ is selectedfrom the group consisting of alkyl, aryl, and heteroaryl moiety bycondensing an alkyl or aryl sulphonyl chloride wherein aryl is selectedfrom the group consisting of substituted phenyl substituted by hydrogen,halogen, alkyl or alkoxy; substituted napthyl substituted by hydrogen ordimethyl amino; and heteroaryl consisting of quinoline with dl 1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide of formula 3

in the presence of a base and an organic solvent to obtain acorresponding 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid amide.
 7. A method as claimed in claim6 wherein the reaction is carried out at a temperature in the range of30° C. to 120° C. for 8 to 24 hours.
 8. A method as claimed in claim 6wherein the halogen is selected from the group consisting of chlorine,bromine fluorine, iodine, and mixtures thereof, alkoxy is selected fromthe group consisting of C₁ to C₁₀ oxy; alkyl is selected from the groupconsisting of C₁ to C₁₀ alkyl, and heteroaryl is selected from the groupconsisting of C₄-C₁₀ heteroaryl.
 9. A method for the preparation of2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)indole-3-carboxylic acid amides comprising reacting a 2-alkyl/arylsulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylicacid ester with methanolic ammonia for 24 to 48 hours to obtain thecorresponding 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid amide.
 10. A process as claimed inclaim 1 wherein the reaction is carried out in the presence of a solventselected from the group consisting of acetone, DMF, THF and dioxane; abase selected from the group consisting of TEA, K₂CO₃. Na₂CO₃, pyridineor any combination thereof and at a temperature in the range of 30° C.to 120° C. and a period of 8 to 24 hours.
 11. A process as claimed inclaim 1 wherein molar ratio of substituted sulphonyl chloride to dlmethyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylate/dl1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-amide is 1:2.
 12. Aprocess as claimed in claim 10 wherein the amount of solvent is in therange of 0.8-2.2 ml per mmol.
 13. A process as claimed in claim 10wherein molar ratio of the base to the dl methyl-1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate/dl 1, 2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide is 1:4.
 14. Apharmaceutical composition comprising a pharmaceutically effectiveamount of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b)indole-3-carboxylic acid ester/amide of formula 1

wherein R is selected from the methyl ester and amide; and R₁ isselected from the group consisting of alkyl, aryl, and heteroarylmoiety, and a pharmaceutically acceptable carrier.
 15. A method for thetreatment of intravascular thrombosis in mammals comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition consisting of a pharmaceuticallyeffective amount of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid amide of formula 1

wherein R is selected from methyl ester and amide; and R₁ is selectedfrom the group consisting of alkyl, aryl and heteroaryl moiety, with apharmaceutically acceptable carrier.
 16. A method for the treatment ofmyocardial ischemia in mammals, comprising by administering to a patientin need thereof a therapeutically effective amount of a pharmaceuticalcomposition consisting of a pharmaceutically effective amount of2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b)indole-3-carboxylic acid ester/amide of formula 1

wherein R is selected from methyl ester and amide; and R₁ is selectedfrom the group consisting of alkyl, aryl and heteroaryl moiety, with apharmaceutically acceptable carrier.
 17. A method for the treatment ofstroke in mammals, comprising administering to a patient in need thereofa therapeutically effective amount of a pharmaceutical compositionconsisting of a pharmaceutically effective amount of 2-alkyl/arylsulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acidester/amide of formula 1

wherein R is selected from methyl ester and amide; and R₁ is selectedfrom the group consisting of alkyl, aryl and heteroaryl moiety, with apharmaceutically acceptable carrier.
 18. A method for treating acondition in mammals, selected from the group consisting of myocardialischemia, intravascular thrombosis and stroke, which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition consisting of a pharmaceuticallyeffective amount of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid ester/amide of formula 1

wherein R is selected from methyl ester and amide; and R₁ is selectedfrom the group consisting of alkyl, aryl and heteroaryl moiety, with orwithout a pharmaceutically acceptable carrier.
 19. The method as claimedin claim 15 wherein the amount of compound of formula 1 is in the rangeof 10 μM to 30 μM per kilogram body weight of subject.
 20. The method asclaimed in claim 16 wherein the amount of compound of formula 1 is inthe range of 10 μM to 30 μM per kilogram body weight of subject.
 21. Themethod as claimed in claim 17 wherein the amount of compound of formula1 is in the range of 10 μM to 30 μM per kilogram body weight of subject.22. The method as claimed in claim 18 wherein the amount of compound offormula 1 is in the range of 10 μM to 30 μM per kilogram body weight ofsubject.